1. Technical Field
The present invention relates generally to compositions and methods for inhibiting IL-17 and IL-23 signaling pathways and for treating or preventing diseases mediated by interleukin-17 and interleukin-23, such as immune-related and inflammatory diseases.
2. Background
Immune-related and inflammatory diseases often involve multistep pathways and multiple biological systems. Intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonizing a detrimental process or pathway, or by stimulating a beneficial process or pathway. The T helper (Th) cell paradigm is widely accepted to explain how the different adaptive immune responses (cellular and humoral) are generated to appropriately respond to diverse types of microbial pathogens. The processes that lead to the differentiation of naive T cells to either IFN-gamma producing Th1 or IL-4 producing Th2 cells were elucidated through the study of the T helper system (Mossman & Coffman) Recently however, several newly discovered members of the Th differentiation pathway have been described. Among these are the TGF-b or IL-10 producing T regulatory cells (Treg or Tr-1, respectively) and IL-17 producing Th17 cells (reviewed in Korn and Gaffen). All of these Th cell types play significant and distinct roles in controlling different infectious agents, tolerance, response resolution and maintenance of immune homeostasis. Differentiation of naive T cells into one specific Th cell type and engagement of effector activity is a highly regulated process where the outcome is determined by a combination of pathogen-derived stimuli and host-derived environmental factors including autocrine and paracrine cytokine profiles that produce positive and negative feedback signals so as to have one type of response predominate (Zhou). The expanded understanding of different Th types has introduced a new paradigm that suggests it is the appropriateness and not the overall magnitude of an immune response that determines the pathogenesis of an organism or its subsequent clearance.
Protracted inflammation brought about by T cell dysregulation is common to various autoimmune diseases. Initially, it was thought that Th1 cells, which mediate responses to intracellular pathogens (e.g. viruses), were responsible for the pathogenesis of various chronic inflammatory diseases, including psoriasis, inflammatory bowel disease, arthritis, autoimmune myocarditis or multiple sclerosis via macrophage activation, excessive cytokine production and induction of self-reactive cytotoxic T lymphocytes (CTL). However, with the recent discovery of IL-23, the role of Th1 cells in autoimmune pathogenesis was brought into question. Th17 cells were first discovered when IL-23-deficient mice (lacking expression of the p19 portion of the heterodimeric cytokine) were shown to be resistant to various models of organ-specific autoimmune disease and exhibited a dramatic diminution in IL-17 expression in a distinct subpopulation of CD4+ T cells. Thus, it was established that Th17 cells and IL-23 fell within an axis of immunity capable of causing tissue destructive responses including recent observations of severe cutaneous, pulmonary and myocardial manifestations in animal models (Rangachari, Mauermann et al. 2006; Carlson, West et al. 2009).
Many immune-related diseases are known and have been extensively studied. There remains a need for therapies where none exists and more effective therapies than those currently available. Such diseases include immune-mediated inflammatory diseases such as asthma, allergic asthma, chronic inflammatory disease (including inflammatory bowel disease, ulcerative colitis, Crohn's disease, arthritis, atopic dermatitis or psoriasis); acute inflammatory disease (e.g. endotoxemia, septicemia, toxic shock syndrome or infectious disease), rheumatoid arthritis, hepatobiliary disease, atherosclerosis, promotion of tumor growth, degenerative joint disease, immune mediated renal disease, adult respiratory disease (ARD), septic shock, multiple organ failure, inflammatory lung injury, chronic obstructive pulmonary disease (COPD), airway hyper-responsiveness, chronic bronchitis, allergic asthma, bacterial pneumonia, psoriasis, eczema, systemic lupus erythematosus (SLE), multiple sclerosis, systemic sclerosis, nephrotic syndrome, organ allograft rejection, graft vs. host disease (GVHD), kidney, lung, heart, etc. transplant rejection, streptococcal cell wall (SCW)-induced arthritis, osteoarthritis, gingivitis/periodontitis, herpetic stromal keratitis, cancers including prostate, renal, colon, ovarian, cervical, leukemia, angiogenesis, restenosis and Kawasaki disease.
There also remains a need for animal models that allow development of therapies for many immune-related diseases. Many infectious disease agents manifest disease not directly from the pathogen but from the host response to the pathogen. In many infectious diseases the “cytokine storm” associated with clearing the infectious agent is responsible for disease manifestation. One such category of infectious agents are those that cause hemorrhagic fever including members of the Arenaviridae, Flaviviridae, Filoviridae, Togaviridae, Arteriviridae, and Bunyaviridae viral families. Animal models that replicate human disease are often not available or perform poorly. For instance, viral replication in an animal model without the associated immunological sequelae seen in infected humans is a poor model for human disease caused by the virus. Animal models that allow perturbation of the IL-23/17 signaling pathways in the context of an infectious disease are particularly needed. Further, animal models that more accurately mimic the human condition will allow development of immunomodulatory therapies that target immune-related diseases, including those beyond the context of infectious diseases.